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Developing novel anti-fibrotic therapeutics for liver disease using bespoke 3D cell culture systems and tissue bioanalysis

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  • Full or part time
    Prof G Aithal
    Dr A Bennett
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

About This PhD Project

Project Description

Integrins are receptor proteins responsible for mechanosensing of tissue stiffness during scarring (fibrosis) in response to injury. Fibrosis in the liver leads to the development of cirrhosis which can progress to cancer, a major cause of mortality. Integrin avα1 is significantly elevated in chronic liver disease and administration of an inhibitor compound shows promise in reducing in fibrosis in a fibrotic mouse model.

This project will provide much-needed information about role of integrins in the process of fibrosis underlying the development of chronic liver disease which is a major global public health challenge. It will also establish integrins as a valid therapeutic target and analyse novel integrin inhibitors with potential to reverse fibrosis.

Background:

Integrin expression is linked to fibroblast proliferation and collagen deposition, causing fibrosis via activation of transforming growth factor TGF. Recently, selective knockout of ɑv integrin in myofibroblastic cells was shown to reduce the progression of fibrosis in vivo suggesting that this may provide a good therapeutic target to selectively inhibit TGF-mediated events which contribute to disease development. In the liver, several integrin heterodimers capable of activating TGF have been described but their role in fibrosis is unknown. The identification of novel compounds which can inhibit integrin activities would be of value as potential therapeutics for fibrosis in chronic liver diseases.

This PhD project will involve:
1) Investigation of the pattern and level of expression of different integrins at the protein level in liver samples from patients with fibrosis,
2) Development of primary human stellate culture system to model fibrosis in vitro and determine expression of integrin during activation,
3) Assessment of the efficacy of integrin inhibitors developed by GSK pharmaceutical research

Research opportunity
Within active hepatology research groups in University of Nottingham: Nottingham Digestive Diseases Centre, FRAME and Nottingham BRC ideally placed for clinical-focussed research with excellent in vitro culture facilities. The project is jointly sponsored and supervised by collaborators at GSK.

Research Environment:
The proposed studentship will be integrated within the Schools of Life Sciences, Medicine and Chemistry where strong partnerships are already forged via the University Research Priority Area focus in ‘Chronic inflammatory diseases’. These are established areas of research excellence: Nottingham Digestive Diseases centre includes the gastrointestinal and liver disorders theme of Nottingham BRC involves (60 researchers; 95 translational studies); the School of Biosciences is rated 2nd on research power and 1st for research environment in the REF2014; research in the School of Chemistry (160 port-graduate students, 60 post-doctoral researchers) was judged to be 95% world-leading in REF2014. This project is also closely aligned with projects within the Nottingham Molecular Pathology Node specialising in translational research in lung and liver diseases. Together the supervisors have a strong background in the techniques involved and track record of collaboration and co-supervision. The project also utilises the established link between GSK and the highly rated School of Chemistry MSci course in which students already develop a valuable resource of novel compounds as potential integrin inhibitors for industry.

Supervisors:
Professor Guruprasad P Aithal
Dr Andrew Bennett
Professor Simon Macdonald
Dr Jane Grove

Applications are invited from potential and recent UK or EU graduates.

The successful applicant will have a strong interest in matrix biology and a drive to study the signalling involved in the development of fibrotic disease
• Knowledge of integrin biology, TGFB signalling, and their role in fibrosis would be an advantage

Key skills may include:
• Experience in aseptic tissue culture techniques or primary cell culture
• Experience in standard cell biology techniques used to isolate and measure expression of proteins/genes (e.g. western blotting; immunoprecipitation and associated techniques)
• The ability to develop and refine in vitro assays to interrogate effects of inhibitors on cellular signalling and response
• Willingness to work across boundaries as part of a prestigious collaboration between University of Nottingham and industrial partners at GSK

Applications should be in the form of a detailed CV and a covering letter. The CV should contain the names and contacts (including e-mails) of two referees, and the type, class and grade (or that predicted) of your degree.

Please send your application to Miss Bethany Robinson, Nottingham Digestive Diseases Centre, E floor, West Block Block, Queen’s Medical Centre, Nottingham, NG7 2UH.
Email: [Email Address Removed]
Tel: 0044 115 823 1149

For informal enquiries please contact Dr Jane Grove ([Email Address Removed]).

Interviews will be held on Thursday 24th May 2018.


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